Delivery Device and Method

ABSTRACT

A nasal delivery device for and method of delivering substance to the middle meatus in a nasal cavity of a subject in the treatment of a condition, in particular an inflammatory or infectious condition, thereof, the delivery device comprising: a nosepiece unit including a nosepiece for fitting to a nostril of a subject and a nozzle through which substance is in use delivered to the respective nasal cavity; and a delivery unit for delivering substance through the nozzle of the nosepiece; wherein the delivery device is configured to provide for deposition of a significant fraction of the delivered dose on, around and in the vicinity of the middle meatus.

The present invention relates to a delivery device for and a method oftreating conditions of the nasal airway, in particular inflammatory orinfectious conditions relating to the middle meatus, such asrhinosinusitis (RS), including acute rhinosinusitis (ARS) and chronicrhinosinusitis (CRS), polyposis, sinus pains, auto-immune diseases,including viral, bacterial, allergic and non-allergic diseases, and thecommon cold.

RS is a prevalent disease, with CRS being the most common chronicdisease in the US, with 10 to 15% of the population being affected (US,Vital Health Statistics). In Europe, about 10% of the population sufferfrom CRS and about 2 to 3% suffer from polyposis, with thus 20 to 30% ofsubjects with CRS also having polyposis.

The pathology of RS and polyposis generally stems from the middlemeatus, where the sinus ostia open to the nasal cavity. In subjects withCRS, the mucosal lining becomes swollen, and, if polyps develop, thepolyps obstruct the middle meatus and often the olfactory cleft whichopens to the olfactory region. As the polyps develop, the polypsnormally extend downwards and backwards, though sometimes forwards. Theobstruction becomes more pronounced with polyp size and is always moreprominent in the upper parts of the nose.

Currently, treatment is by drops as delivered by pipette or aerosolsprays as delivered by a conventional spray pump. Studies have shownthat conventional sprays are inadequate in reaching the middle meatus.Drops can reach the middle meatus, but this requires rigorous patientcompliance, insofar as the patients have to adopt particular bodypositions during delivery, such as the “Mecca” position, which arerarely respected.

It is an aim of the present invention to provide a delivery device forand method of delivering substance to the middle meatus, particularly inthe treatment of inflammatory or infectious conditions relating to themiddle meatus, in particular ARS, CRS and polyposis.

The present inventors have recognized that an increased delivery ofsubstance to the posterior region of the nasal airway, and in particularthe upper posterior region of the nasal airway, as illustrated in FIG.1, relative to the anterior region of the nasal airway, surprisinglyprovides for improved delivery to the middle meatus, and in particularin subjects with nasal polyps.

The posterior region of the nasal airway is that region which isposterior of the nasal valve NV, as illustrated in FIG. 1. The nasalvalve comprises the anterior bony cavum which contains inferiorturbinate erectile tissue and septal erectile tissue, which aresupported respectively by compliant ala tissue and the rigidcartilaginous septum (Cole). These elements combine to form a dynamicvalve, which extends over several millimetres, that adjusts nasalairflow, and is stabilized by cartilage and bone, modulated by voluntarymuscle and regulated by erectile tissue. The lumen of the nasal valve isthe section of narrowest cross-sectional area between the posterior andanterior regions of the nasal airway, and is much longer and narrowerdorsally than ventrally, and this lumen defines a triangular entrancewhich extends to the piriform region of the bony cavum. The nasal valveis lined in its anterior part with transitional epithelium, with agradual transition posterior to respiratory epithelium. The nasal valveand anterior vestibule define roughly the anterior one-third of thenose.

The posterior region of the nasal airway is that region which is linedwith respiratory epithelium, which is ciliated, and olfactoryepithelium, which comprises nerves which extend downwards through thecribiform plate CP from the olfactory bulb, whereas the anterior regionof the nasal airway is that region which is lined with squamousepithelium, which is not ciliated, and transitional epithelium. Theolfactory epithelium extends on both the lateral and medial sides of thenasal airway, and typically extends downwards about 1.5 to 2.5 cm.

The upper posterior region is the region above the inferior meatus IM,as illustrated in FIG. 1, and encompasses the middle turbinate, themiddle meatus, the sinus ostia in infundibulum (ostia to maxillary,frontal and ethmoidal sinuses), the olfactory region, and the upperbranches of the trigeminal nerve, and is that region which includesveins which drain to the venous sinuses that surround the brain.

As illustrated in FIG. 1, the posterior region of the nasal airway isthe nasal region posterior of an imaginary vertical plane VERT which islocated at a position corresponding to the lower angle of the anteriornasal aperture (aperture piriformis), which corresponds substantially toone-quarter of the distance between the anterior nasal spine AnS, whichis a pointed projection at the anterior extremity of the intermaxillarysuture, and the posterior nasal spine PnS, which is the sharp posteriorextremity of the nasal crest of the hard palate and represents thetransition between the nose and the nasopharynx, which corresponds to adistance posterior of the anterior nasal spine AnS of between about 13mm and about 14 mm (Rosenberger defines the distance between theanterior nasal spine AnS and the posterior nasal spine PnS as being 56mm in eighteen year old boys and 53.3 mm in eighteen year old girls).

As further illustrated in FIG. 1, the upper region of the nasal airwayis an upper segment of the nasal airway which is bounded by thecribiform plate CP and a horizontal plane HORIZ which is located at aposition corresponding to one-third of the distance between the nasalfloor NF of the nasal airway and the cribiform plate CP, whichcorresponds to a height of typically between about 13 and about 19 mmabove the nasal floor NF (Zacharek et al define the distance from thenasal floor NF to the cribiform plate CP as 46+/−4 mm).

The upper posterior region is thus that upper posterior region which isbounded by the above-defined vertical and horizontal planes VERT, HORIZ.

In one aspect the present invention provides a nasal delivery device fordelivering substance, typically as a formulation, to the middle meatusin a nasal cavity of a subject in the treatment of a condition, inparticular an inflammatory or infectious condition, thereof, thedelivery device comprising: a nosepiece unit including a nosepiece forfitting to a nostril of a subject and a nozzle through which substanceis in use delivered to the respective nasal cavity; and a delivery unitfor delivering substance through the nozzle of the nosepiece; whereinthe delivery device is configured such that at least 50% of the dose asinitially deposited in the nasal airway is deposited in a region of thenasal cavity which is posterior of the nasal valve and at least 30% ofthe dose as initially deposited in the nasal cavity is deposited in anupper posterior region of the nasal cavity which is posterior of thenasal valve and above the inferior meatus.

In another aspect the present invention provides a nasal delivery devicefor delivering substance, typically as a formulation, to the middlemeatus in a nasal cavity of a subject in the treatment of a condition,in particular an inflammatory or infectious condition, thereof, thedelivery device comprising: a nosepiece unit including a nosepiece forfitting to a nostril of a subject and a nozzle through which substanceis in use delivered to the respective nasal cavity; and a delivery unitfor delivering substance through the nozzle of the nosepiece; whereinthe nozzle provides for delivery of the substance as at least one liquidjet or an aerosol spray having a cone angle of not more than about 50degrees.

In a further aspect the present invention provides a nasal deliverydevice for delivering substance, typically as a formulation, to a nasalairway of a subject, comprising: a nosepiece unit including a nosepiecefor fitting to a nostril of a subject, the nosepiece including a nozzlethrough which substance is in use delivered to the respective nasalcavity; and a delivery unit for delivering substance through the nozzleof the nosepiece.

In a still further aspect the present invention provides a method ofdelivering substance, typically as a formulation, to the middle meatusin a nasal cavity of a subject in the treatment of a condition, inparticular an inflammatory or infectious condition, thereof, the methodcomprising the steps of: fitting a nosepiece unit to one nostril of asubject, the nosepiece unit including a nosepiece which is inserted intothe one nostril of a subject and a nozzle through which substance isdelivered to the respective nasal cavity; and delivering substancethrough the nozzle into the nasal cavity, wherein at least 50% of thedose as initially deposited in the nasal airway is deposited in a regionof the nasal cavity which is posterior of the nasal valve and at least30% of the dose as initially deposited in the nasal cavity is depositedin an upper posterior region of the nasal cavity which is posterior ofthe nasal valve and above the inferior meatus.

In still another aspect the present invention provides a method ofdelivering substance, typically as a formulation, to the middle meatusin a nasal cavity of a subject in the treatment of a condition, inparticular an inflammatory or infectious condition, thereof, the methodcomprising the steps of: fitting a nosepiece unit to one nostril of asubject, the nosepiece unit including a nosepiece which is into the onenostril of a subject and a nozzle through which substance is deliveredto the respective nasal cavity; and delivering substance through thenozzle into the nasal cavity, wherein the nozzle provides for deliveryof the substance as at least one liquid jet or an aerosol spray having acone angle of not more than about 50 degrees.

In yet another aspect the present invention provides a method ofdelivering substance, typically as a formulation, to a nasal airway of asubject, comprising the steps of: fitting a nosepiece unit to onenostril of a subject, the nosepiece unit including a nosepiece which isinserted into the one nostril of a subject and a nozzle through whichsubstance is delivered to the respective nasal cavity; and deliveringsubstance through the nozzle of the nosepiece unit into the nasalcavity.

In still yet another aspect the present invention provides a nasaldelivery device for and method of delivering substance, typically as aformulation, to the middle meatus in a nasal cavity of a subject in thetreatment of a condition, in particular an inflammatory or infectiouscondition, thereof, the delivery device comprising: a nosepiece unitincluding a nosepiece for fitting to a nostril of a subject and a nozzlethrough which substance is in use delivered to the respective nasalcavity; and a delivery unit for delivering substance through the nozzleof the nosepiece; wherein the delivery device is configured to providefor deposition of a significant fraction of the delivered dose on,around and in the vicinity of the middle meatus.

In one embodiment the present invention provides for the treatment ofrhinosinusitis (RS), including acute rhinosinusitis (ARS) and chronicrhinosinusitis (CRS).

In one embodiment the present invention provides for the treatment ofnasal polyps.

CRS and polyposis are observed in subjects with Cystic Fibrosis, bothpaediatric and adult subjects, where the condition is associated with anabnormality in the nasal mucosa, and the present invention hasparticular application in relation to such treatment.

In one embodiment the present invention provides for the treatment ofsinus pains.

In one embodiment the present invention provides for the treatment ofauto-immune diseases, including viral, bacterial, allergic andnon-allergic diseases, such as antigen-induced diseases.

In one embodiment the present invention provides for the treatment ofthe common cold.

In one embodiment the substance comprises a steroid, such asfluticasone, budesonide, mometasone, betamethasone, beclomethasone,triamcinolone and flunisoloide, and the pharmaceutically-acceptablesalts and derivatives thereof.

In one embodiment the substance comprises a decongestant, such asephedrine, pseudoephedrine, oxymetazoline, xylometazoline, phenylephrineand phenylpropanolamine, and the pharmaceutically-acceptable salts andderivatives thereof.

In one embodiment the substance comprises a non-steroidalanti-inflammatory, such as sodium cromoglycate, nedocromil sodium,ibuprofen, salicylates, indomethacin, dexketoprofen, ketoprofen,fenbufen, naproxen and diclofenac, and the pharmaceutically-acceptablesalts and derivatives thereof.

In one embodiment the substance comprises an anti-cholinergic, such asipratropium, tiotropium and oxitropium, and thepharmaceutically-acceptable salts and derivatives thereof.

In one embodiment the substance comprises an anti-histamine, such asazelastine, loratidine, brompheniramine, chlorpheniramine, mizolastine,promethazine, doxylamine, desloratidine, triprolidine, clemastine,fexofenadine, cetirizine and levocetirizine, and thepharmaceutically-acceptable salts and derivatives thereof.

In one embodiment the substance comprises a mast cell stabilizer, suchas ketotifen, and the pharmaceutically-acceptable salts and derivativesthereof.

In one embodiment the substance comprises a leukotriene antagonist, suchas zafirlukast and montelukast, and the pharmaceutically-acceptablesalts and derivatives thereof.

In one embodiment the substance comprises a diuretic, such as frusemide,and the pharmaceutically-acceptable salts and derivatives thereof.

In one embodiment the substance comprises an anti-biotic, such asamikacin, azithromycin, aztreonan, cefazolin, cefepine, cefonicid,cefaperazone, cefotaxime, cefotetan, cefoxitin, ceftazidime,ceftizoxime, ceftriaxone, cerfuroxime, cephapirin, ciprofloxacin,clindamycin, doxycycline, erthyromycin lactobionate, gentamicin,kanamycin, linezolid, mezlocillin, mupirocin, nafcillin, netilmicin,neomycin, oxacillin, paromomycin, piperacillin, streptomycin,ticarcillin, tobramycin and vancomycin, and thepharmaceutically-acceptable salts and derivatives thereof.

In one embodiment the substance comprises an anti-fungal, such aspolyene macrolides, tetraene macrolides, pentaenic macrolides,fluorinated pryimidines, imidazoles, triazoles, azoles, halogenatedphenolic ethers, thiocarbamates, allylamines, sterol inhibitor,amphotericin B, ketoconazole, itraconazole, saperconazole, voriconazole,flucytosine, miconazole, fluconazole, griseofulvin, clotrimazole,econazole, terconazole, butoconazole, oxiconazole, sulconazole,ciclopirox olamine, haloprogin, tolnaftate, naftifine, terbinafinehydrochloride, morpholines, nystatin, natamycin, butenafine, undecylenicacid, Whitefield's ointment, propionic acid, caprylic acid, and thepharmaceutically-acceptable salts and derivatives thereof.

In one embodiment the substance comprises an immuno-modulator. In oneembodiment the immuno-modulator comprises an antigen, such as anallergen, in particular a polypeptide antigen or any part, small orlarge, of an antigen, where natural or synthesized. In anotherembodiment the immuno-modulator comprises a nucleic acid molecule orpolypeptide for modulation or suppression of the immune response or oneor more steps in the immune cascade or process.

In one embodiment the substance comprises an ionic transport controlsubstance which acts to normalize or counteract an imbalance in theionic transport across the cell membranes, such as benzalkoniumchloride.

In one embodiment the substance can comprise a biofilm-destroying agentwhich acts to destroy bacterial biofilms which can tend to form insubjects with conditions associated with nasal inflammation andinfection. In one embodiment the biofilm-destroying agent comprises ananti-biotic, such as tetracycline, linezolid and moxifloxacin, and thepharmaceutically-acceptable salts and derivatives thereof. In anotherembodiment the biofilm-destroying agent comprises a disinfectant, suchas chlorohexidine, and the pharmaceutically-acceptable salts andderivatives thereof. In a further embodiment the biofilm-destroyingagent can be included as a preservative, such as benzalkonium chloride,within the substance formulation.

In preferred embodiments the substances can be administered separatelyor in any combination, individually or simultaneously, within a singleformulation.

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIG. 1 illustrates the segmentation of a nasal cavity in accordance witha preferred embodiment of the present invention;

FIG. 2 schematically illustrates a nasal delivery device in accordancewith a first embodiment of the present invention;

FIG. 3 illustrates the delivery device of FIG. 2 where operative todeliver a dose of substance into the nasal airway of the subject;

FIG. 4 schematically illustrates a nasal delivery device in accordancewith a second embodiment of the present invention;

FIG. 5 illustrates the delivery device of FIG. 4 where operative todeliver a dose of substance into the nasal airway of the subject;

FIG. 6 schematically illustrates a nasal delivery device in accordancewith a third embodiment of the present invention;

FIG. 7 illustrates the delivery device of FIG. 6 where operative todeliver a dose of substance into the nasal airway of the subject;

FIG. 8 schematically illustrates a nasal delivery device in accordancewith a fourth embodiment of the present invention;

FIG. 9 illustrates the delivery device of FIG. 8 where operative todeliver a dose of substance into the nasal airway of the subject;

FIG. 10 schematically illustrates a nasal delivery device in accordancewith a fifth embodiment of the present invention; and

FIG. 11 illustrates the delivery device of FIG. 10 where operative todeliver a dose of substance into the nasal airway of the subject.

FIGS. 2 and 3 illustrate a nasal delivery device in accordance with afirst embodiment of the present invention.

The delivery device comprises a housing 15, a nosepiece unit 17 forfitting in a nasal cavity of a subject, and a mouthpiece 19 throughwhich the subject exhales to actuate the delivery device.

The nosepiece unit 17 comprises a nosepiece 20, in this embodiment afrusto-conical element, for guiding the nosepiece unit 17 into a nasalcavity of the subject and being configured both to provide a fluid-tightseal with the nares of the nostril and at least obstruct, in thisembodiment close, the nasal passage at a position therealong, in thisembodiment at a position corresponding substantially to the nasal valve,thereby obstructing the anterior one-third of the nasal passage andleaving open the posterior two-thirds of the nasal cavity, asillustrated in FIG. 3.

In this embodiment the nosepiece 20 is further configured such asmechanically to open the nasal valve, thereby facilitating access to theposterior two-thirds of the nasal cavity, and in particular the middlemeatus.

The nosepiece unit 17 further comprises an outlet unit 21 for deliveringsubstance, which has an anti-inflammatory or other therapeutic effect onthe middle meatus, into the nasal cavity of the subject and to themiddle meatus, in this embodiment for the treatment of one or both ofRS, in particular CRS, and polyposis. In this embodiment the substancecomprises a formulation containing a nasal steroid, such as fluticasone.

In this embodiment the outlet unit 21 comprises a delivery channel 23which is in fluid communication with the mouthpiece 19, such that an airflow is delivered into the nasal airway of the subject on exhalation bythe subject through the mouthpiece 19, and a nozzle 25 for deliveringsubstance into the nasal cavity of the subject.

In this embodiment the nozzle 25 is configured to deliver a jet, as acolumn of substance. In delivering the substance as a jet, the substancecan be more readily directed at the middle meatus, typically asobstructed by RS and nasal polyps.

In this embodiment the nozzle 25 is configured to deliver a liquid jet,but in another embodiment could be configured to deliver a powder jet.

The delivery device further comprises a substance supply unit 29 fordelivering metered doses of the substance, which is fluidly connected tothe nozzle 25 to deliver the substance from the nosepiece unit 17, inthis embodiment as a jet.

In this embodiment the substance supply unit 29 comprises a mechanicaldelivery pump.

In this embodiment the substance supply unit 29 is a multi-dose unit fordelivering a plurality of metered doses of the substance. In anotherembodiment the substance supply unit 29 could be a single-dose unit fordelivering a single metered dose of the substance.

The substance supply unit 29 is pre-primeable, in this embodiment byloading a resilient element, and includes a breath-actuated releasemechanism 31 which, when triggered, releases the resilient element andactuates the substance supply unit 29 to deliver a metered dose of thesubstance through the nozzle 25.

In this embodiment the release mechanism 31 is configured to causeactuation of the substance supply unit 29 on generation of apredetermined pressure at the delivery channel 23.

The generation of a raised pressure in the nasal cavity acts to expandthe region of the nasal cavity anterior of the middle meatus andposterior of the nasal valve, with one or both of inflamed mucosa orpolyps in the upper region of the nasal cavity acting to provide aresistance to the anteriorly-delivered air flow and thus providing anincreased pressure anterior of the middle meatus. This expansion of theregion of the nasal cavity anterior of the middle meatus facilitatesaccess to the middle meatus and also reduces the deposition of substancein the anterior region. Deposition in the anterior region has been shownto lead to crusting and bleeding, which is particularly uncomfortable.In addition, the increased pressure in the nasal cavity acts to forcesubstance into ducts and channels leading to the sinuses, which can beblocked by mucosal inflammation and polyps.

Operation of the delivery device will now be described hereinbelow withreference to FIG. 3 of the accompanying drawings.

The nosepiece unit 17 is first inserted into one of the nasal cavitiesof a subject until the nosepiece 20 abuts the nares of the nostril suchas to establish a fluid-tight seal therewith, at which point the distalend of the outlet unit 21 extends about 2 cm into the nasal cavity ofthe subject such as to engage with and expand the nasal valve, and themouthpiece 19 is gripped in the lips of the subject.

The subject then begins to exhale through the mouthpiece 19, whichexhalation acts to close the oropharyngeal velum of the subject anddrive an air flow through the delivery channel 23 of the outlet unit 21,with the air flow passing into the one nasal cavity, around theposterior margin of the nasal septum and out of the other nasal cavity,thereby achieving a bi-directional air flow through the nasal airway ofthe subject, in the manner as described in WO-2000/051672. Where themiddle meatus is obstructed, the flow is restricted and along the floorof the nose, but, as discussed hereinabove, acts to generate a pressurein the nasal cavity which acts to expand the constriction at the middlemeatus.

In this embodiment, when the pressure developed at the delivery channel23 reaches a predetermined value, the release mechanism 31 is triggeredto actuate the substance supply unit 29 to deliver a metered dose of thesubstance to the nozzle 25 and into the nasal cavity of the subject as ajet.

In this embodiment the delivery device is configured such that at least50% of the dose as initially deposited in the nasal cavity is depositedin a region of the nasal cavity which is posterior of the nasal valve,and at least 30% of the dose as initially deposited in the nasal cavityis deposited in an upper posterior region of the nasal cavity which isposterior of the nasal valve and above the inferior meatus. With suchdelivery, improved deposition is obtained on the middle meatus, inparticular at the site of nasal polyps.

In preferred embodiments the delivery device is configured such that atleast 55%, more preferably at least 60%, still more preferably at least65% and yet more preferably 70% of the dose as initially deposited inthe nasal cavity is deposited in the region posterior of the nasalvalve.

In preferred embodiments the delivery device is configured such that atleast 35%, more preferably at least 40%, still more preferably at least45% and yet more preferably 50% of the dose as initially deposited inthe nasal cavity is deposited in the upper posterior region of the nasalcavity.

In this embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the pump unit29.

In one alternative embodiment the nozzle 25 could be configured todeliver a plurality of jets. This configuration still facilitatesdelivery through the nasal valve to the middle meatus as compared toconventional sprays which have a wide cone angle.

In one embodiment the contralateral nostril can be partially or whollyobstructed, such as to promote the generation of a raised pressure inthe nasal cavity into which substance is to be delivered. In oneembodiment the contralateral nostril can be obstructed by applying apressure to the lateral nare of the contralateral nostril. In anotherembodiment the nosepiece unit 17 can include a second nosepiece 20 whichis configured to be fitted in the other nostril of the subject such asto obstruct the same.

FIGS. 4 and 5 illustrate a nasal delivery device in accordance with asecond embodiment of the present invention.

The delivery device of this embodiment is very similar to the deliverydevice of the above-described first embodiment, and thus, in order toavoid unnecessary duplication of description, only the differences willbe described in detail, with like reference signs designating likeparts.

The delivery device of this embodiment differs from that of theabove-described first embodiment in further comprising an oralexhalation breath-actuatable gas supply unit 33 for delivering a gasflow through the delivery channel 23 of the outlet unit 21 in responseto exhalation by a subject, and in that the mouthpiece 19 is in fluidcommunication with the gas supply unit 33 and not the delivery channel23 of the outlet unit 21, whereby a gas flow is delivered to thedelivery channel 23 of the outlet unit 21, and hence the nasal airway ofthe subject, in response to exhalation through the mouthpiece 19.

Operation of the delivery device is the same as for the above-describedfirst embodiment, with a gas flow being delivered to the deliverychannel 23 of the outlet unit 21 in response to exhalation through themouthpiece 19.

In one alternative embodiment the release mechanism 31 could be amanually-actuated unit and the mouthpiece 19 omitted.

FIGS. 6 and 7 illustrate a nasal delivery device in accordance with athird embodiment of the present invention.

The delivery device of this embodiment is quite similar to the deliverydevice of the above-described first embodiment, and thus, in order toavoid unnecessary duplication of description, only the differences willbe described in detail, with like reference signs designating likeparts.

The delivery device of this embodiment differs from that of theabove-described first embodiment in the release mechanism 31 being amanually-actuated unit and the mouthpiece 19 and the delivery channel 23of the outlet unit 21 being omitted. With this configuration, a gas flowis not delivered into the nasal cavity of the subject, but thesubstance, in being delivered as a jet, acts to provide for targeteddelivery to the middle meatus without any deposition anterior of thenasal valve, which would be experienced with a conventional nasal spray.

Operation of the delivery device is the same as for the above-describedfirst embodiment, except that a gas flow is not delivered into the nasalcavity.

FIGS. 8 and 9 illustrate a nasal delivery device in accordance with afourth embodiment of the present invention.

The delivery device comprises a housing 115, a nosepiece unit 117 forfitting in a nasal cavity of a subject, and a mouthpiece 119 throughwhich the subject exhales to actuate the delivery device.

The nosepiece unit 117 comprises a nosepiece 120, in this embodiment afrusto-conical element, for guiding the nosepiece unit 117 into a nasalcavity of the subject and being configured both to provide a fluid-tightseal with the nares of the nostril and at least obstruct, in thisembodiment close, the nasal passage at a position therealong, in thisembodiment at a position corresponding substantially to the nasal valve,thereby obstructing the anterior one-third of the nasal cavity andleaving open the posterior two-thirds of the nasal cavity, asillustrated in FIG. 9.

In this embodiment the nosepiece 120 is further configured such asmechanically to open the nasal valve, thereby facilitating access to theposterior two-thirds of the nasal cavity, and in particular the middlemeatus.

The nosepiece unit 117 further comprises an outlet unit 121 fordelivering substance, which has an anti-inflammatory or othertherapeutic effect on the middle meatus, into the nasal cavity of thesubject and to the middle meatus, for the treatment of one or both ofRS, in particular CRS, and polyposis. In this embodiment the substancecomprises a formulation containing a nasal steroid, such as fluticasone.

In this embodiment the outlet unit 121 comprises a delivery channel 123which is in fluid communication with the mouthpiece 119 such that an airflow is delivered into and through the nasal airway of the subject onexhalation by the subject through the mouthpiece 119, and a nozzle 125for delivering the substance into the nasal cavity of the subject.

In this embodiment the nozzle 125 is configured to deliver an aerosolspray, either as a liquid or powder aerosol, here having arelatively-narrow cone angle.

In one embodiment the cone angle is not more than about 50 degrees,preferably not more than about 40 degrees, more preferably not more thanabout 35 degrees, still more preferably not more than about 30 degrees,yet more preferably not more than about 25 degrees, still yet morepreferably not more than about 20 degrees, and still yet more preferablynot more than about 15 degrees.

In delivering the substance as an aerosol spray with a narrow coneangle, the substance can be more readily directed at the middle meatusas obstructed by RS and nasal polyps.

The delivery device further comprises a substance supply unit 129 fordelivering metered doses of the substance, which is fluidly connected tothe nozzle 125 to deliver the substance from the nosepiece unit 117, inthis embodiment as an aerosol spray.

In this embodiment the substance supply unit 129 comprises a mechanicaldelivery pump, in particular a liquid delivery pump or a powder deliverypump, which delivers metered doses of substance on actuation thereof.

In another embodiment the substance supply unit 129 could comprise a drypowder delivery unit which delivers metered doses of a substance, as adry powder, on actuation thereof.

In a further embodiment the substance supply unit 129 could comprise anaerosol canister for delivering metered volumes of a propellant,preferably a hydrofluoroalkane (HFA) propellant or the like, containingsubstance on actuation thereof.

In another alternative embodiment the substance supply unit 129 couldcomprise a nebulizer which delivers metered doses of a substance, as anaerosol spray, on actuation thereof.

In this embodiment the substance supply unit 129 is a multi-dose unitfor delivering a plurality of metered doses of the substance. In anotherembodiment the substance supply unit 129 could be a single-dose unit fordelivering a single metered dose of the substance.

The substance supply unit 129 is pre-primeable, in this embodiment byloading a resilient element, and includes a breath-actuated releasemechanism 131 which, when triggered, releases the resilient element andactuates the substance supply unit 129 to deliver a metered dose of thesubstance through the nozzle 125.

In this embodiment the release mechanism 131 is configured to causeactuation of the substance supply unit 129 on generation of apredetermined pressure at the delivery channel 123.

The generation of a raised pressure in the nasal cavity acts to expandthe region of the nasal cavity anterior of the middle meatus andposterior of the nasal valve, with one or both of inflamed mucosa orpolyps in the upper region of the nasal cavity acting to provide aresistance to the anteriorly-delivered air flow and thus providing anincreased pressure anterior of the middle meatus. This expansion of theregion of the nasal cavity anterior of the middle meatus facilitatesaccess to the middle meatus and also reduces the deposition of substancein the anterior region. Deposition in the anterior region has been shownto lead to crusting and bleeding, which is particularly uncomfortable.In addition, the increased pressure in the nasal cavity acts to forcesubstance into ducts and channels leading to the sinuses, which can beblocked by mucosal inflammation and polyps.

Operation of the delivery device will now be described hereinbelow withreference to FIG. 9 of the accompanying drawings.

The nosepiece unit 117 is first inserted into one of the nasal cavitiesof a subject until the nosepiece 120 abuts the nares of the nostril,such as to establish a fluid-tight seal therewith, at which point thedistal end of the outlet unit 121 extends about 2 cm into the nasalcavity of the subject such as to engage with and expand the nasal valve,and the mouthpiece 119 is gripped in the lips of the subject.

The subject then begins to exhale through the mouthpiece 119, whichexhalation acts to close the oropharyngeal velum of the subject anddrive an air flow through the delivery channel 123 of the outlet unit121, with the air flow passing into the one nasal cavity, around theposterior margin of the nasal septum and out of the other nasal cavity,thereby achieving a bi-directional air flow through the nasal airway ofthe subject, in the manner as described in WO-2000/051672. Where themiddle meatus is obstructed, the flow is restricted and along the floorof the nose, but, as discussed hereinabove, acts to generate a pressurein the nasal cavity which acts to expand the constriction at the middlemeatus.

In this embodiment, when the pressure developed at the delivery channel123 reaches a predetermined value, the release mechanism 131 istriggered to actuate the substance supply unit 129 to deliver a metereddose of the substance to the nozzle 125 and into the nasal cavity of thesubject as an aerosol spray.

In this embodiment the delivery device is configured such that at least50% of the dose as initially deposited in the nasal cavity is depositedin a region of the nasal cavity which is posterior of the nasal valve,and at least 30% of the dose as initially deposited in the nasal cavityis deposited in an upper posterior region of the nasal cavity which isposterior of the nasal valve and above the inferior meatus. With suchdelivery, improved deposition is obtained on the middle meatus, inparticular at the site of nasal polyps.

In preferred embodiments the delivery device is configured such that atleast 55%, more preferably at least 60%, still more preferably at least65% and yet more preferably 70% of the dose as initially deposited inthe nasal cavity is deposited in the region posterior of the nasalvalve.

In preferred embodiments the delivery device is configured such that atleast 35%, more preferably at least 40%, still more preferably at least45% and yet more preferably 50% of the dose as initially deposited inthe nasal cavity is deposited in the upper posterior region of the nasalcavity.

In this embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the pump unit129.

In one embodiment the contralateral nostril can be partially or whollyobstructed, such as to promote the generation of a raised pressure inthe nasal cavity into which substance is to be delivered. In oneembodiment the contralateral nostril can be obstructed by applying apressure to the lateral nare of the contralateral nostril. In anotherembodiment the nosepiece unit 117 can include a second nosepiece 120which is configured to be fitted in the other nostril of the subjectsuch as to obstruct the same.

FIGS. 10 and 11 illustrate a nasal delivery device in accordance with afifth embodiment of the present invention.

The delivery device comprises a housing 215, and a nosepiece unit 217for fitting in a nasal cavity of a subject and into which the subjectnasally exhales to actuate the delivery device.

The nosepiece unit 217 comprises a nosepiece 220, in this embodiment afrusto-conical element, for guiding the nosepiece unit 217 into a nasalcavity of the subject and being configured both to provide a fluid-tightseal with the nares of the nostril and at least obstruct, in thisembodiment close, the nasal passage at a position therealong, in thisembodiment at a position corresponding substantially to the nasal valve,thereby obstructing the anterior one-third of the nasal cavity andleaving open the posterior two-thirds of the nasal cavity, asillustrated in FIG. 11.

In this embodiment the nosepiece 220 is further configured such asmechanically to open the nasal valve, thereby facilitating access to theposterior two-thirds of the nasal cavity, and in particular the middlemeatus.

The nosepiece unit 217 further comprises an outlet unit 221 fordelivering substance, which has an anti-inflammatory or othertherapeutic effect on the middle meatus, into the nasal cavity of thesubject and to the middle meatus, for the treatment of one or both ofRS, in particular CRS, and polyposis. In this embodiment the substancecomprises a formulation containing a nasal steroid, such as fluticasone.

In this embodiment the outlet unit 221 comprises a communication channel223 which is in fluid communication with the nasal cavity of thesubject, such as to enable nasal exhalation to be detected through thegeneration of an increased pressure thereat, and a nozzle 225 fordelivering a metered dose of substance into the nasal cavity of thesubject.

In this embodiment the nozzle 225 is configured to deliver a jet, as acolumn of substance, either of liquid or powder. In delivering thesubstance as a jet, the substance can be more readily directed at themiddle meatus as obstructed by RS and nasal polyps.

The delivery device further comprises a substance supply unit 229 fordelivering metered doses of the substance, which is fluidly connected tothe nozzle 225 to deliver the substance from the nosepiece unit 217, inthis embodiment as a jet.

In this embodiment the substance supply unit 229 comprises a mechanicaldelivery pump.

In this embodiment the substance supply unit 229 is a multi-dose unitfor delivering a plurality of metered doses of the substance. In anotherembodiment the substance supply unit 229 could be a single-dose unit fordelivering a single metered dose of the substance.

The substance supply unit 229 is pre-primeable, in this embodiment byloading a resilient element, and includes a breath-actuated releasemechanism 231 which, when triggered by nasal exhalation, releases theresilient element and actuates the substance supply unit 229 to delivera metered dose of the substance through the nozzle 225.

In this embodiment the release mechanism 231 is configured to causeactuation of the substance supply unit 229 on generation of apredetermined pressure at the communication channel 223, which isdeveloped in response to nasal exhalation.

The generation of a raised pressure in the nasal cavity acts to expandthe nasal cavity, and in particular the region including the middlemeatus which represents a region of increased resistance when includingone or both of inflamed mucosa or polyps. This expansion of the regionof the nasal cavity including the middle meatus facilitates access tothe middle meatus and also reduces the deposition of substance in theanterior region. Deposition in the anterior region has been shown tolead to crusting and bleeding, which is particularly uncomfortable. Inaddition, the increased pressure in the nasal cavity acts to forcesubstance into ducts and channels leading to the sinuses, which can beblocked by mucosal inflammation and polyps.

Operation of the delivery device will now be described hereinbelow withreference to FIG. 11 of the accompanying drawings.

The nosepiece unit 217 is first inserted into one of the nasal cavitiesof a subject until the nosepiece 220 abuts the nares of the nostril,such as to establish a fluid-tight seal therewith, at which point thedistal end of the outlet unit 221 extends about 2 cm into the nasalcavity of the subject such as to engage and expand the nasal valve.

The subject then begins to exhale nasally, which exhalation acts togenerate an increased pressure in the one nasal cavity which acts toexpand the constriction at the middle meatus. In this embodiment themouth of the subject can be closed, or the mouth can remain open and thetongue be positioned such as to prevent oral exhalation, as illustratedin FIG. 11.

In this embodiment, when the pressure developed at the communicationchannel 223 reaches a predetermined value, the release mechanism 231 istriggered to actuate the substance supply unit 229 to deliver a metereddose of the substance to the nozzle 225 and into the nasal cavity of thesubject as a jet.

In this embodiment the delivery device is configured such that at least50% of the dose as initially deposited in the nasal cavity is depositedin a region of the nasal cavity which is posterior of the nasal valve,and at least 30% of the dose as initially deposited in the nasal cavityis deposited in an upper posterior region of the nasal cavity which isposterior of the nasal valve and above the inferior meatus. With suchdelivery, improved deposition is obtained on the middle meatus, inparticular at the site of nasal polyps.

In preferred embodiments the delivery device is configured such that atleast 55%, more preferably at least 60%, still more preferably at least65% and yet more preferably 70% of the dose as initially deposited inthe nasal cavity is deposited in the region posterior of the nasalvalve.

In preferred embodiments the delivery device is configured such that atleast 35%, more preferably at least 40%, still more preferably at least45% and yet more preferably 50% of the dose as initially deposited inthe nasal cavity is deposited in the upper posterior region of the nasalcavity.

In this embodiment, where the delivery device is a multi-dose device,the device is ready for further use following priming of the pump unit229.

In one alternative embodiment the nozzle 225 could be configured todeliver a plurality of liquid jets. This configuration still facilitatesdelivery through the nasal valve to the middle meatus as compared toconventional sprays which have a wide cone angle.

In one embodiment the contralateral nostril can be partially or whollyobstructed, such as to promote the generation of a raised pressure inthe nasal cavity into which substance is to be delivered. In oneembodiment the contralateral nostril can be obstructed by applying apressure to the lateral nare of the contralateral nostril. In anotherembodiment the nosepiece unit 217 can include a second nosepiece 220which is configured to be fitted in the other nostril of the subjectsuch as to obstruct the same.

Finally, it will be understood that the present invention has beendescribed in its preferred embodiment and can be modified in manydifferent ways without departing from the scope of the invention asdefined by the appended claims.

In one modification, the delivery device of the fifth-describedembodiment could be modified to include first and second nosepiece units217 for fitting to the respective nostrils of the subject. With thisconfiguration, an increased pressure is generated in both of the nasalcavities and substance can be delivered to both of the nasal cavities ina single operation of the delivery device.

In another modification, the delivery device of the fifth-describedembodiment could be modified, in the manner of the fourth-describedembodiment, such that the outlet unit 221 provides for an aerosol spray,either as a liquid or powder aerosol.

In preferred embodiments the delivery devices are configured to deliveran air flow through one nostril of a subject at such a pressure as toflow around the posterior margin of the nasal septum and out of theother nostril of the subject, thereby achieving bi-directional deliverythrough the nasal cavities as disclosed in WO-A-00/51672, the content ofwhich is herein incorporated by reference. In alternative embodimentsthe delivery device could be configured to deliver an air flow at areduced pressure which is not sufficient to achieve bi-directionaldelivery through the nasal cavities. Such embodiments are stilladvantageous as compared to known delivery devices in providing forvelum closure and being capable of achieving targeted delivery.

REFERENCES

1. Cole, P, The Respiratory Role of the Upper Airways, a selectiveclinical and pathophysiological review. 1993, Mosby-Year Book Inc.ISBN1.55664-390-X.

2. Rosenberger, H, Growth and Development of the Naso-Respiratory Areain Childhood, PhD Thesis, Laboratory of Anatomy, School of Medicine,Western Reserve University, Presented to the Annual Meeting of theAmerican Laryngological, Rhinological and Otological Society,Charleston, S.C., USA, 1934.

3. Zacharek, M A et al, Sagittal and Coronal Dimensions of the EthmoidRoof: A Radioanatomic Study, Am 3 Rhinol 2005, Vol 19, pages 348 to 352.

1-252. (canceled)
 253. A method of delivering fluticasone to the middlemeatus in one, first nasal cavity of a subject in the treatment of nasalpolyps, the method comprising: fitting a first nosepiece unit to one,first nostril of a subject, wherein the first nosepiece unit includes anosepiece which is inserted into the first nostril, and a nozzle throughwhich fluticasone is delivered to the first nasal cavity from a firstsubstance supply unit; providing a first mouthpiece unit which includesa mouthpiece, wherein the mouthpiece of the first mouthpiece unit isfluidly connected to the nosepiece of the first nosepiece unit; thesubject exhaling through the mouthpiece of the first mouthpiece unit soas to cause closure of the oropharyngeal velum of the subject anddeliver an air flow through the first nostril, around the posteriormargin of the nasal septum and out of the other, second nostril of thesubject; and delivering, during exhalation through the mouthpiece of thefirst mouthpiece unit, a liquid aerosol spray comprising a dose offluticasone from the first substance supply unit through the nozzle ofthe first nosepiece unit into the first nasal cavity; wherein at least50% of the dose as initially deposited in the nasal airway is depositedin a region of the first nasal cavity which is posterior of the nasalvalve and at least 30% of the dose as initially deposited in the nasalairway is deposited in an upper posterior region of the first nasalcavity which is posterior of the nasal valve and above the inferiormeatus.
 254. The method claim 253, wherein inserting the nosepieceobstructs the nasal valve so as to obstruct a nasal passage anteriorlyof the nasal valve.
 255. The method of claim 253, wherein inserting thenosepiece closes the nasal valve, preventing deposition of fluticasoneanteriorly of the nasal valve.
 256. The method of claim 253, wherein theaerosol spray has a cone angle of not more than 50 degrees.
 257. Themethod of claim 253, wherein the aerosol spray has a cone angle of notmore than 40 degrees.
 258. The method of claim 253, further comprising:manually actuating the substance supply unit to release the dose. 259.The method of claim 253, wherein at least 55% of the dose as initiallydeposited in the nasal airway is deposited in the region posterior ofthe nasal valve.
 260. The method of claim 253, wherein at least 60% ofthe dose as initially deposited in the nasal airway is deposited in theregion posterior of the nasal valve.
 261. The method of claim 253,wherein at least 35% of the dose as initially deposited in the nasalairway is deposited in the upper posterior region thereof.
 262. Themethod of claim 253, wherein at least 40% of the dose as initiallydeposited in the nasal airway is deposited in the upper posterior regionthereof.
 263. The method of claim 253, wherein at least 45% of the doseas initially deposited in the nasal airway is deposited in the upperposterior region thereof.
 264. The method of claim 253, wherein at least50% of the dose as initially deposited in the nasal airway is depositedin the upper posterior region thereof.
 265. The method of claim 253,wherein the nosepiece is inserted into the first nostril such that thenosepiece extends into the nasal valve and provides for expansion of thenasal valve.
 266. The method of claim 253, further comprising: fitting asecond nosepiece unit to the second nostril, wherein the secondnosepiece unit includes a nosepiece which is inserted into the secondnostril, and a nozzle through which fluticasone is delivered to thesecond nasal cavity from a second substance supply unit; providing asecond mouthpiece unit which includes a mouthpiece, wherein themouthpiece of the second mouthpiece unit is fluidly connected to thenosepiece of the second nosepiece unit; the subject exhaling through themouthpiece of the second mouthpiece unit so as to cause closure of theoropharyngeal velum of the subject and deliver an air flow through thesecond nostril, around the posterior margin of the nasal septum and outof the first nostril; and delivering, during exhalation though themouthpiece of the second mouthpiece unit, a liquid aerosol spraycomprising a dose of fluticasone from the second substance supply unitthrough the nozzle of the second nosepiece unit into the second nasalcavity; wherein at least 50% of the dose as initially deposited in thenasal airway is deposited in a region of the second nasal cavity whichis posterior of the nasal valve and at least 30% of the dose asinitially deposited in the nasal airway is deposited in an upperposterior region of the second nasal cavity which is posterior of thenasal valve and above the inferior meatus.
 267. The method of claim 266,wherein a single nosepiece unit is used as the first and secondnosepiece units, a single mouthpiece unit is used as the first andsecond mouthpiece units, and a single substance supply unit is used asthe first and second substance supply units.
 268. The method of claim267, wherein the single substance supply unit comprises a multi-dosepump unit for delivery a plurality of metered doses of fluticasone, eachdose being delivered in response to a single actuation of the multi-dosepump unit.
 269. A method of delivering fluticasone to the middle meatusof each of first and second nasal cavities of a subject in the treatmentof nasal polyps, the method comprising: fitting a nosepiece unit to one,first nostril of a subject, wherein the nosepiece unit includes anosepiece which is inserted into the first nostril to extend into thenasal valve and expand the nasal valve, and a nozzle through whichfluticasone is delivered to the first nasal cavity from a substancesupply unit; providing a mouthpiece unit which includes a mouthpiece,wherein the mouthpiece is fluidly connected to the nosepiece; thesubject exhaling through the mouthpiece so as to cause closure of theoropharyngeal velum of the subject and deliver an air flow through thefirst nostril, around the posterior margin of the nasal septum and outof the other, second nostril of the subject; and delivering, duringexhalation though the mouthpiece, a liquid aerosol spray comprising adose of fluticasone from the substance supply unit through the nozzleinto the first nasal cavity; wherein at least 50% of the dose asinitially deposited in the nasal airway is deposited in a region of thefirst nasal cavity which is posterior of the nasal valve and at least30% of the dose as initially deposited in the nasal airway is depositedin an upper posterior region of the first nasal cavity which isposterior of the nasal valve and above the inferior meatus; fitting thenosepiece unit to the second nostril, wherein the nosepiece is insertedinto the second nostril to extend into the nasal valve and expand thenasal valve; the subject exhaling through the mouthpiece so as to causeclosure of the oropharyngeal velum of the subject and deliver an airflow through the second nostril, around the posterior margin of thenasal septum and out of the first nostril; and delivering, duringexhalation through the mouthpiece, a liquid aerosol spray comprising adose of fluticasone from the substance supply unit through the nozzleinto the second nasal cavity; wherein at least 50% of the dose asinitially deposited in the nasal airway is deposited in a region of thesecond nasal cavity which is posterior of the nasal valve and at least30% of the dose as initially deposited in the nasal airway is depositedin an upper posterior region of the second nasal cavity which isposterior of the nasal valve and above the inferior meatus.
 270. Amethod of delivering fluticasone to the middle meatus in one, firstnasal cavity of a subject in the treatment of nasal polyps, the methodcomprising: fitting a nosepiece unit to one, first nostril of a subject,wherein the nosepiece unit includes a nosepiece which is inserted intothe first nostril to extend into the nasal valve and expand the nasalvalve, and a nozzle through which fluticasone is delivered to the firstnasal cavity from a multi-dose pump unit; providing a mouthpiece unitwhich includes a mouthpiece, wherein the mouthpiece is fluidly connectedto the nosepiece; the subject exhaling through the mouthpiece so as tocause closure of the oropharyngeal velum of the subject and deliver anair flow through the first nostril, around the posterior margin of thenasal septum and out of the other, second nostril of the subject; anddelivering, during exhalation through the mouthpiece, a liquid aerosolspray comprising a metered dose of fluticasone from the multi-dose pumpunit through the nozzle of the nosepiece unit into the first nasalcavity; wherein at least 50% of the dose as initially deposited in thenasal airway is deposited in a region of the first nasal cavity which isposterior of the nasal valve and at least 30% of the dose as initiallydeposited in the first nasal airway is deposited in an upper posteriorregion of the first nasal cavity which is posterior of the nasal valveand above the inferior meatus.